(�)-1-(2,5-Dimethoxy-4-ethylthiophenyl)-2-aminopropane (ALEPH-2), a novel putative anxiolytic agent lacking affinity for benzodiazepine sites and serotonin-1A receptors

Abstract

Serotonergic behavioral responses, effects on motor activity and core temperature, and binding properties of the novel putative anxiolytic amphetamine derivative (+/-)1-(2,5-dimethoxy-4-ethylthio-phenyl)-2-aminopropane (ALEPH-2), were examined in rodents in order to elucidate the mechanism underlying its anxiolytic-like effect. After peripheral administration in rats, ALEPH-2 induced some symptoms of the serotonergic syndrome, e.g. forepaw treading and flat body posture. Additionally, a decrease in motor activity was observed. No significant effects on the number of head shakes were observed after injection, although high inter-subject variability was noted. Higher doses of ALEPH-2, in the range exhibiting anxiolytic properties (4mg/kg), elicited significant hypothermia in mice. The affinity of the drug for 5-HT2A/2C receptors ([3H]ketanserin sites) was in the nanomolar range (Ki = 173 nM), whereas for 5-HT1A, benzodiazepine sites, and GABAA receptors, the affinity was micromolar of lower. Based on these results the mechanism of action and the anxiolytic-like properties of ALEPH-2 are discussed.

Effect of Hallucinogens on Unconditioned Behavior

“…In other words, hallucinogens enhance the threatening nature of the unfamiliar test environment, but hallucinogen-treated animals are more likely to explore the BPM chambers once the stimuli associated with the apparatus become less threatening due to habituation. Other groups have reported that hallucinogens reduce locomotor activity in a novel environment (Tilson et al 1975; Hillegaart et al 1996; Reyes-Parada et al 1996; Scorza et al 1996; Palenicek et al 2010) but have no effect or increase activity in a familiar environment (Tilson et al 1975; Ouagazzal et al 2001; Filip et al 2004; Zaniewska et al 2009; Baisley et al 2012). Hallucinogens increase center avoidance in novel and familiar settings, suggesting they probably also act by enhancing the fear of open spaces (agoraphobia), which is normally displayed by rodents even after habituation.…”

Ibogaine Acute Administration in Rats Promotes Wakefulness, Long-Lasting REM Sleep Suppression, and a Distinctive Motor Profile

“…The number of rearings was taken as an index of the vertical exploratory behavior to evaluate the animal habituation to the environment. Serotonin syndrome-like continuous behaviors such as tremor, flat body posture, piloerection, hind limb abduction, and Straub tail ( Haberzettl et al, 2013 ) were scored using a graded scale: 0, absent; 1, equivocal; 2, present; and 3, intense ( Spanos and Yamamoto, 1989 ; Reyes-Parada et al, 1996 ; Baumann et al, 2001b ). In the case of forepaw treading (an intermittent behavior), an additive score of 1 was given every time the animal displayed this conduct.…”